Rheumatology: Current Research

Rheumatology: Current Research
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Research Article - (2016) Volume 6, Issue 2

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Prevalence of MTX Intolerance in Rheumatoid Arthritis- A 3 Year Prospective Hospital Based Study

Mushtaq Ahmad*, Fayaz Sofi and Ashiq Parray
Rheumatology Division of Medicine, SKIMS Srinagar, Kashmir, India, E-mail: fayazkanjwal@rediffmail.com
*Corresponding Author: Mushtaq Ahmad, Associate Professor, Rheumatology Division of Medicine, SKIMS Srinagar, Kashmir, India Email:

Abstract

Background: Rheumatoid arthritis is most common inflammatory arthritis. Methotrexate is backbone of treatment regimens.

Objective: To determine the prevalence of Methotrexate intolerance in rheumatoid arthritis.

Material and Methods: 150 patients of RA including 120 females and 30 males attending rheumatology services of hospital from December 2012 to December 2015 were prescribed MTX as per approved protocol and were followed for Methotrexate Intolerance Severity Score (MISS).

Results: Out of 150 patients of RA on methotrexate (MTX), 21 (14%) were found to have MISS ≥ 6.

Conclusion: MISS is an important tool for application in RA to know Methotrexate intolerance and timely intervention to mitigate the same in order to prevent the incompliance of an otherwise very effective DMARD for RA.

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Keywords: Methotrexate (MTX); Methotrexate Intolerance Severity Score (MISS); Rheumatoid Arthritis (RA)

Introduction

RA is the most common inflammatory arthritis affecting 0.5-1% of the global population [1-3]. If not treated in time and adequately can lead to various deformities particularly to hands. After the introduction of DMARDS including MTX deformities like swan neck, z deformity and boutonniere deformities are no longer seen now. MTX is the backbone of almost all combination treatment regimens of RA and has resulted in enhanced efficacy over MTX alone, without added increases in side effects [4-7]. To improve its compliance MTX intolerance parameters are looked for and required mitigating actions taken to improve its compliance.

Materials and Methods

150 patients of RA including 120 females and 30 males attending Rheumatology services of hospital from December 2012 to December 2015 were prescribed MTX as per approved standard and were followed for MTX intolerance as per validated Methotrexate intolerance severity score questionnaire. MTX intolerance features were enquired at each visit which was of 4-6 weekly. Base line stomach ache, nausea, vomiting, behavioural symptoms before starting MTX were enquired. If features of stomach ache, nausea, vomiting, restlessness and irritability were absent. A score 0 was given for mild score of 1; moderate score of 2 and for severe score of 3 was given. For each individual MISS item pre, post and associative features were enquired. The above questions were enquired at each visit for at least 3 months for patients who got enrolled in last trimester of study. Methotrexate intolerance was considered if MISS was ≥ 6. Informed consent was taken from patients and ethical committee of the hospital.

Results

Out of 150 patients of RA on MTX 21 (14%) were found to have MISS ≥ 6; out of 21 patients 18 were on oral MTX and 3 were on parental MTX. 6 (4.9%) had stomach ache as anticipatory symptom on oral MTX and 3 (11.1%) on parental MTX. 18 (14.6%) on oral MTX were having stomach ache after MTX and in 11.1% after parental MTX (p 0.024). 12 (9.7%) of patients on oral MTX were having stomach ache as associative symptom, 3 (11.1%) on parental MTX were having stomach ache as associative symptom. 15 (12.2%) patients on oral MTX were having nausea as anticipatory symptom, 3 (11.1%) on parental MTX were having nausea as associative symptom. After MTX intake 31.7% of patients had nausea on oral MTX and 11.1% on parental MTX (p 0.019). 22.5% of patients were found to have nausea as associative symptom on oral MTX, 11.1% were found to have nausea as associative symptom on parental MTX. 2.4% patients on oral MTX were found to have vomiting as anticipatory symptom. None on parental MTX were found to have vomiting as anticipatory symptom. 12.2% on oral MTX were having vomiting after MTX and 11.1% of patients were having vomiting after parental MTX. 12 (9.8%) patients on oral MTX were found to have restlessness after oral MTX and 11.1% were found to have restlessness after parental MTX. 9.8% of patients were found to have irritability after oral MTX (Tables 1-6).

Sex Route Total
Oral Parentral
Female 9375.60% 27100.00% 12080.00%
Male 30
24.40%		 0
0.00%		 30
20.00%
Total 123
100.00%		 27
100.00%		 150
100.00%

Table 1: Showing gender distribution of patients.

  Route Total
Oral Parentral
Nil (0) 117
95.1%		 24
88.9%		 141
94.0%
Mild (1) 6
4.9%		 3
11.1%		 9
6.0%
Total 123
100.0%		 27
100.0%		 150
100.0%

Table 2: Showing number and percentage of RA patients experience anticipatory stomach ache 1 cell (25.0%) have expected less than 5; The minimum expected is 1.62.

  Value Df Asymp. Sig. (2-sided) Exact Sig. (2-s9ided) Exact Sig. (1-sided)
Pearson Chi-Square 1.525a 1 0.217    
Continuity Correctionb 0.620 1 0.431    
Likelihood ratio 1.306 1 0.253    
Fisher’s Exact test       0.206 0.206
Linear-by-linear association 1.515 1 0.218    
N of valid cases 150        

Table 2a: C computed only for a 2X2 table.

  Route Total
Oral Parentral
Nil (0) 105
85.4%		 24
88.9%		 129
86.0%
Mild (1) 15
12.2%		 0
0.0%		 15
10%
Moderate (2) 3
2.4%		 3
11.1%		 6
4%
Total 123
100%		 27
100%		 150
100%

Table 3: Showing number and percentage of patient having stomach ache after MTX.

  Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 7.487a 2 .024
Likelihood ratio 9.147 2 .010
Linear-by-linear association .256 1 .613
N of valid cases 150    

Table 3a: Chi-Square Tests.

  Route Total
Oral Parentral
Nil (0) 111
90.2%		 24
88.9%		 135
90.0%
Mild (1) 9
7.3%		 3
11.1%		 12
8.0%
Severe (3) 3
2.4%		 0
0.0%		 3
2.0%
Total 123
100.0%		 27
100.0%		 150
100.0%

Table 4: Showing number and percentage of patients having stomach ache as associative symptom.

  Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 1.061a 2 .588
Likelihood ratio 1.560 2 .458
Linear-by-linear association 114 1 .736
N of valid cases 150    

Table 4a: 3 cells (50.0%) have expected less than 5. The minimum expected is 54.

  Route Total
Oral Parentral
Nil (0) 108
87.80%		 24
88.90%		 132
88.00%
Mild (1) 12
9.80%		 0
0.00%		 12
8.00%
Moderate (2) 3
2.40%		 3
11.10%		 6
4.00%
Total 123
100.00%		 27
100.00%		 150
100.00%

Table 5: Showing number and percentage of patients having nausea as anticipatory symptom.

  Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 6.800a 2 .033
Likelihood ratio 7.928 2 .019
Linear-by-linear association .591 1 .442
N of valid cases 150    

Table 5a: 3 cells (50.0%) have expected less than 5. The minimum expected is 1.08.

  Route Total
Oral Parentral
Nil (0) 84
68.3%		 24
88.9%		 108
72.0%
Mild (1) 18
14.6%		 0
0.0%		 18
12.0%
Moderate (2) 15
12.2%		 0
0.0%		 15
10.0%
Severe (3) 6
4.9%		 3
11.1%		 9
6.0%
Total 123
100.0%		 27
100.0%		 150
100.0%

Table 6: Showing number and percentage of patients having nausea after MTX intake.

  Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 9.982a 3 .019
Likelihood ratio 15.544 3 .001
Linear-by-linear association 1.122 1 .290
N of valid cases 150    

Table 6a: Chi-Square Tests.

Discussion

MTX was found in 21(14%) RA patients in our study compared to 10.4% of 249 patients of RA seen in a study by Bulatovic Calasan, et al. [8]. 14.4% on oral MTX were having MISS ≥ 6 as compared to 11.1% on parental MTX in our study. It was more on parental than on oral MTX in the study conducted by Bulatovic Calasan, et al. (20.6 Vs. 6.2%) [8]. In our study, 31.7% patients on oral MTX and 11.1 % on parental MTX were having nausea after MTX intake. In the study conducted by Bulatovic Calasan, et al. 32% was found to have nausea. It was found in 14.4-28% in the study conducted by Jacobs, et al. and Kremer et al. [9,10]. 19.5% of RA on oral and 11.1% on parental MTX were having gastrointestinal symptoms and behavioural symptoms though not qualifying MISS ≥ 6. Keeping the usefulness of MTX and mitigation by various procedures in view use of MISS is recommended to apply for patients of RA on MTX. The mitigation procedures include change of route of MTX administration, folic acid administration, antiemetic and behavioural therapy (Tables 7-14) [11,12].

  Route Total
Oral Parentral
Nil (0) 93
77.5%		 24
88.9%		 117
79.6%
Mild (1) 18
15.0%		 0
0.0%		 18
12.2%
Moderate (2) 6
5.0%		 3
11.1%		 9
6.1%
Severe (3) 3
2.5%		 0
0.0%		 3
2.0%
Total 120
100.0%		 27
100.0%		 147
100.0%

Table 7: Showing number and percentage of patients having nausea as associative symptom.

  Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 6.429a 3 .093
Likelihood ratio 10.018 3 .018
Linear-by-linear association .506 1 .477
N of valid cases 147    

Table 7a: 4 cells (50.0%) have expected less than 5. The minimum expected is 55.

  Route Total
Oral Parentral
Nil (0) 120
97.6%		 27
100.0%		 147
98.0%
Mild (2) 3
2.4%		 0
0.0%		 3
2.0%
Total 123
100.0%		 27
100.0%		 150
100.0%

Table 8: Showing number and percentage of patients having vomiting as anticipatory symptom.

  Value df Asymp. Sig. (2-sided) Exact Sig. (2-sided) Exact Sig. (1-sided)
Pearson Chi-Square .627a 1 .412    
Continuity correction .004 1 .952    
Likelihood ratio 1.204 1 .273    
Fisher’s exact test       1.000 .549
Linear-by-linear association .667 1 .414    
N of valid cases 150        

Table 8a: 2 cells (50.0%) have expected less than 5 the minimum expected is 54; Computed only for a 2X2 table.

  Route Total
Oral Parentral
Nil (0) 108
87.8%		 24
88.9%		 132
88.0%
Mild (1) 6
4.9%		 3
11.1%		 9
6.0%
Moderate (2) 9
7.3%		 0
0.0%		 9
6.0%
Total 123
100.0%		 27
100.0%		 150
100.0%

Table 9: Showing number and percentage of patients having vomiting after MTX intake.

  Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 3.412a 2 0.182
Likelihood ratio 4.788 2 .091
Linear-by-linear association .580 1 .449
N of valid cases 150    

Table 9a: 2 cells (33.3%) have expected less than 5. The minimum expected is 1.62.

  Route Total
Oral Parentral
Nil (0) 111
90.2%		 24
88.9%		 135
90.0%
Mild (2) 12
9.8%		 3
11.1%		 15
10.0%
Total 123
100.0%		 27
100.0%		 150
100.0%

Table 10: Showing number and percentage of patients having restlessness after MTX intake.

  Value df Asymp. Sig. (2-sided) Exact Sig. (2-sided) Exact Sig. (1-sided)
Pearson Chi-Square .045a 1 .823    
Continuity correction
Likelihood ratio		 .000
.044		 1
1		 1.000
.834		    
Fisher’s exact test       .735 .531
Linear-by-linear association .045 1 .832    
N of valid cases 150        

Table 10a: 1 cell (25.0%) has expected less than 5. The minimum expected is 2.70; Computed only for 2X2 table.

  Route Total
Oral Parentral
Nil (0) 111
90.2%		 24
88.9%		 135
90.0%
Mild (1) 12
9.8%		 3
11.1%		 15
10.0%
Total 123
100.0%		 27
100.0%		 150
100.0%

Table 11: Showing number and percentage of patients having irritability due to MTX intake.

  Value df Asymp. Sig. (2-sided) Exact Sig. (2-sided) Exact Sig. (1-sided)
Pearson Chi-Square .045 1 .832    
Continuity correction .000 1 1.000    
Likelihood ratio .044 1 .834    
Fisher’s exact test       .735 .531
Linear-by-linear association .045 1 .832    
N of valid cases 150        

Table 11a: 1 cell (25.0%) has expected less than 5. The minimum expected is 2.70; Computed only for 2X2 table.

Oral
Parentral
Total		 Route Total
Nil (0) 123
100.0%		 27
100.0%		 150
100.0%
Total 123
100.0%		 27
100.0%		 150
100.0%

Table 12: Depicting number of patients refusal to take MTX.

  Route Total
Oral Parentral
hcqs 81
65.9%		 18
66.7%		 99
66.0%
lefno 3
2.4%		 3
11.1%		 6
4.0%
Mps 27
22.0%		 3
11.1%		 30
20.0%
ssz 12
9.8%		 3
11.1%		 15
10.0%
Total 123
100.0%		 27
100.0%		 150
100.0%

Table 13: Showing number and percentage of patients taking drugs in addition to MTX.

  Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 5.506a 3 .138
Likelihood ratio 4.704 3 .195
N of valid cases 150    

Table 13 a: 3 cells (37.5%) have expected less than 5. The minimum expected is 1.08.

  Route Total
Oral Parentral
0 81
65.9%		 21
77.8		 102
68.0%
1 3
2.4%		 0
0.0		 3
2.0%
2 6
4.9%		 0
0.0		 6
4.0%
3 9
7.3%		 3
11.1%		 12
8.0%
4 6
4.9%		 0
0.0		 6
4.0%
6 9
7.3%		 0
0.0%		 9
6.0%
7 3
2.4%		 0
0.0%		 3
2.0%
9 6
4.9%		 3
11.1%		 9
6.0%
Total score  123
100.0%		 27
100.0%		 150
100.0%

Table 14: showing minimum to maximum MISS (0-9).

  Value Df Asymp. Sig. (2-sided)
Pearson Chi-Square 8.222a 7 .313
Likelihood ratio 12.741 7 .079
Linear-by-linear association .195 1 .659
N of valid cases 150    

Table 14a: 11 cells (68.8%) have expected less than 5. The minimum expected is 54.

Conclusion

Application of MISS reveals that in addition to known gastrointestinal symptoms including abdominal pain, nausea, vomiting after MTX therapy, anticipatory and associative features which are believed to be conditioned phenomenon could hamper MTX compliance. Timely intervention like change of route, folic acid, antiemetic, behavioural therapy can prevent the MTX incompliance and provide a smooth path for an otherwise effective DMARD for RA.

References

  1. Wolfe AM (1968) The epidemiology of rheumatoid arthritis: a review. I. Surveys. Bull Rheum Dis 19: 518-523.
  2. Ngel A, Roberts Jburch (1966) Rheumatoid arthiritis in adults in the united states,1960-1962.In vital and health statistics,series11,data from national health survey,number 17.Washington,DC,National center for health statistics.
  3. Mikkelsen WM, Dodge HJ, Duff IF, Kato H (1967) Estimates of the prevalence of rheumatic diseases in the population of Tecumseh, Michigan, 1959-60. J Chronic Dis 20: 351-369.
  4. O'Dell JR, Haire CE, Erikson N, Drymalski W, Palmer W, et al. (1996) Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 334: 1287-1291.
  5. Möttönen T, Hannonen P, Leirisalo-Repo M, Nissilä M, Kautiainen H, et al. (1999) Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 353: 1568-1573.
  6. Lipsky PE, Heijde VDM, ST Clair EW (2000) INFLIXIMAB and mtx in the treatment of RA:anti-tumor necrosis factor trial in RA with concomitant therapy study group.N Eng J med 343:1594-1602.
  7. St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, et al. (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 50: 3432-3443.
  8. Äalasan MB, van den Bosch OF, Creemers MC, Custers M, Heurkens AH, et al. (2013) Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis. Arthritis Res Ther 15: 217.
  9. Bakker MF, Jacobs JW, Welsing PM, Verstappen SM, Tekstra J, et al. (2012) Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med 156: 329-339.
  10. Kremer JM, Phelps CT (1992) Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum 35: 138-145.
  11. Visser K,Loza KW,Martinez-Lopez JA, Sallict C, Trudeau J, et al. (2009) Multinational evidence based recommendations for the use of Methotrexate in rheumatic disorders with a focus on rheumatoid arthiritis :integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative .Ann Rheum Dis 68:1068-1093.
  12. Bulavotic M,Heijstek MW, Verkaaik M, Van Dijkhuizen EH , Armbrust W,et al. (2011) High prevalence of Methotrexate intolerance in juvenile idiopathic arthiritis:development and validation of a methorexate intolerance severity score . Arthiritis Rheum63:2007-2013.
Citation: Ahmad M, Sofi F, Parray A (2016) Prevalence of MTX Intolerance in Rheumatoid Arthritis- A 3 Year Prospective Hospital Based Study. Rheumatology (Sunnyvale) 6:195.

Copyright: © 2016 Ahmad M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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